Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025145
Angiopoietin-like 4 (ANGPTL4) expression is increased in wound tissue and contributes to wound healing. However, the underlying mechanisms are not fully understood. Here, we demonstrate that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during wound healing in mice. Increased Angptl4 expression is positively correlated with increased expressions of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1. Each of these molecules induces Angptl4 expression in mouse EpSCs. RNA sequencing of EpSCs derived from wild-type and Angptl4 knockout (Angptl4–/–) mice reveals altered expressions of genes involved in the cell cycle and cell proliferation in Angptl4–/– EpSCs, including a decrease in cyclin E2/A2/B1 and cyclin-dependent kinase 1 (Cdk1) expression; an increase in Cdk inhibitor 2a (Cdkn2a) and Cdkn2b expression; and a decrease in the prolactin (PRL) family members Prl2a1, Prl8a1, Prl8a9, and Prl8a6. Mechanistic studies reveal that ANGPTL4 stimulates EpSC proliferation via PRL8a6-mediated upregulation of cyclins A2/E2/B1 and Cdk1, downregulation of Cdkn2a, and acceleration of cell cycle progression from the G1 to the S and G2 phases. In vivo studies demonstrate that Prl8a6 mRNA is upregulated by ANGPTL4 in mouse periwound tissue during skin wound healing. Knockdown of Angptl4 or Prl8a6 in periwound skin tissue impairs EpSC proliferation and delays wound re-epithelialization. In conclusion, our study demonstrates that, after skin injury, elevated levels of proinflammatory cytokines and growth factors in periwound tissue stimulate Angptl4 expression in EpSCs and that ANGPTL4 promotes EpSC proliferation by increasing Prl8a6 expression, thereby accelerating wound re-epithelialization.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024202
Dorsal root ganglion (DRG) neurons are responsible for the primary detection and transmission of peripheral noxious stimuli, mainly pain and itch. However, as two distinct noxious sensations, how DRG neurons respond differently to and code pain and itch is still an attractive topic. Here, we investigate the response and activation spectrum of DRG neurons under peripheral pain and itch stimuli using in vivo two-photon calcium imaging and find differences in the response intensity to pain and itch between multisensory neurons (both pain and itch) and single-sensory neurons (either pain or itch). In addition, single-cell RNA sequencing (scRNA-seq) is used to reveal the heterogeneity of distinct subpopulations on the basis of their expressions of pain- or itch-related marker genes and to determine the similarities and differences in their transcriptomic changes under chronic pain and itch. Our results show that primary sensory neurons with different sensory patterns respond differently to the same nociceptive stimuli. Additionally, distinct clusters of neurons exhibit unique transcriptomic changes in the development of chronic pain and itch, which may offer new insights for treating these conditions.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026102
Necrosis by sodium overload (NECSO) is a distinct cell death modality induced by the chemical regulator necrocide 1 (NC1), which targets the transient receptor potential melastatin 4 (TRPM4) channel to drive excessive sodium influx and potassium efflux. This unique necrosis is characterized by the exchange of monovalent ions, a restrained ATP supply, redox disorder and a final membrane rupture as main features. Real-time monitoring of metabolic and redox causality during the whole process in living cells has been technically challenging. To bridge this gap, we integrate an advanced toolset of genetically encoded fluorescent sensors to monitor monovalent ions, energy metabolites, and redox equivalents with high spatiotemporal resolution. By directing these sensors to specific subcellular compartments, we successfully capture the real-time choreography of potassium loss specifically induced by NC1 via TRPM4. Furthermore, we establish a precise detection paradigm for evaluating energy currency by integrating sensors for NADH and ATP that are capable of subcellular imaging. We observe general and rapid NADH accumulation along with an ATP shortage in the mitochondria and cytosol. A concomitant reduction in mitochondrial oxidative stress is observed. This study not only elucidates the metabolic progression of a peculiar type of necrosis but also establishes a robust methodological framework for applying genetically encoded sensors to broader physiological and toxicological research.
Acta Biochimica et Biophysica Sinica•2024•DOI: 10.3724/abbs.2024070
Epidermal stem cells (EpSCs) play a vital role in skin wound healing through re-epithelialization. Identifying chemicals that can promote EpSC proliferation is helpful for treating skin wounds. This study investigates the effect of morroniside on cutaneous wound healing in mice and explores the underlying mechanisms. Application of 10‒50 μg/mL of morroniside to the skin wound promotes wound healing in mice. In vitro studies demonstrate that morroniside stimulates the proliferation of mouse and human EpSCs in a time- and dose-dependent manner. Mechanistic studies reveal that morroniside promotes the proliferation of EpSCs by facilitating the cell cycle transition from the G1 to S phase. Morroniside increases the expression of β-catenin via the glucagon-like peptide-1 receptor (GLP-1R)-mediated PKA, PKA/PI3K/AKT and PKA/ERK signaling pathways, resulting in an increase in cyclin D1 and cyclin E1 expression, either directly or by upregulating c-Myc expression. This process ultimately leads to EpSC proliferation. Administration of morroniside to mouse skin wounds increases the phosphorylation of AKT and ERK, the expressions of β-catenin, c-Myc, cyclin D1, and cyclin E1, as well as the proliferation of EpSCs, in periwound skin tissue, and accelerates wound re-epithelialization. These effects of morroniside are mediated by the GLP-1R. Overall, these results indicate that morroniside promotes skin wound healing by stimulating the proliferation of EpSCs via increasing β-catenin expression and subsequently upregulating c-Myc, cyclin D1, and cyclin E1 expressions through GLP-1R signaling pathways. Morroniside has clinical potential for treating skin wounds.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2024169
Peripheral nerve injury (PNI) can transform primary somatosensory neurons to a regenerative state. However, the details of the transcriptomic changes associated with the nerve regeneration of somatosensory neurons remain unclear. In this study, single-cell RNA sequencing (scRNA-seq) is conducted on mouse dorsal root ganglion (DRG) cells after the early stage of nerve injury on day 3 after chronic constriction injury (CCI). We observe that a novel CCI-induced neuronal population (CIP) emerge and express high levels of activating transcription factor (Atf3), a neuronal injury marker. CIP neurons highly express regeneration-associated genes (RAGs) and are enriched in regeneration-related gene ontology (GO) terms, suggesting that these neurons can constitute a pro-regenerative population. Moreover, intercellular communication networks show that CIP neurons closely communicate with satellite glial cells (SGCs) and specifically transmit strong Fgf3-Fgfr1 signaling to SGCs, which could initiate regeneration-associated transcriptional changes in SGCs. We also confirm that regenerative progress occurs at the early stage of nerve injury because immunohistochemistry shows that the expression of ATF3 is significantly increased beginning at 3 days post-CCI and decreased at 1 month post-CCI. Our bioinformatics analysis at single-cell resolution advances the knowledge of regenerative dynamic transcriptional changes in DRG cells after injury and the underlying molecular mechanisms involved.
Acta Biochimica et Biophysica Sinica•2026•DOI: 10.3724/abbs.2026102
Necrosis by sodium overload (NECSO) is a distinct cell death modality induced by the chemical regulator necrocide 1 (NC1), which targets the transient receptor potential melastatin 4 (TRPM4) channel to drive excessive sodium influx and potassium efflux. This unique necrosis is characterized by the exchange of monovalent ions, a restrained ATP supply, redox disorder and a final membrane rupture as main features. Real-time monitoring of metabolic and redox causality during the whole process in living cells has been technically challenging. To bridge this gap, we integrate an advanced toolset of genetically encoded fluorescent sensors to monitor monovalent ions, energy metabolites, and redox equivalents with high spatiotemporal resolution. By directing these sensors to specific subcellular compartments, we successfully capture the real-time choreography of potassium loss specifically induced by NC1 via TRPM4. Furthermore, we establish a precise detection paradigm for evaluating energy currency by integrating sensors for NADH and ATP that are capable of subcellular imaging. We observe general and rapid NADH accumulation along with an ATP shortage in the mitochondria and cytosol. A concomitant reduction in mitochondrial oxidative stress is observed. This study not only elucidates the metabolic progression of a peculiar type of necrosis but also establishes a robust methodological framework for applying genetically encoded sensors to broader physiological and toxicological research.
Chinese Journal of Tissue Engineering Research•2026•DOI: 10.12307/2026.21598
BACKGROUND: In recent years, the involvement of non-apoptotic regulated cell death in the development of ischemic stroke has become a research hotspot. OBJECTIVE: To summarize the roles and action mechanisms of non-apoptotic regulated cell death subroutines such as autophagy, ferroptosis, cuproptosis, disulfidptosis, necroptosis, and pyroptosis in the neuronal damage caused by ischemic stroke. METHODS: Relevant literature on non-apoptotic regulated cell death and ischemic stroke was retrieved from the China National Knowledge Infrastructure and PubMed databases. The search terms included "ischemic stroke, regulated cell death, autophagy, ferroptosis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, alkaliptosis, oxeiptosis, parthanatos, mitochondrial permeability transition-driven necrosis, neutrophil extracellular trap-related death, lysosome-dependent cell death, immunogenic cell death, anoikis" in English and corresponding Chinese terms. Based on inclusion criteria, 176 articles were finally included for analysis and summary. RESULTS AND CONCLUSION: The regulatory mechanisms of non-apoptotic regulated cell death mainly include autophagy, ferroptosis, anoikis, cuproptosis, disulfidptosis, necroptosis, pyroptosis, oxeiptosis, alkaliptosis, parthanatos, mitochondrial permeability transition-driven necrosis, neutrophil extracellular trap-related death, lysosome-dependent cell death, and immunogenic cell death. Autophagy plays a dual regulatory role in neuronal injury after ischemic stroke: under ischemic conditions, autophagy exerts a neuroprotective effect, whereas excessive autophagy during reperfusion can lead to neuronal death. Ferroptosis can aggravate neuronal injury in ischemic stroke through iron overload and lipid peroxidation. Cuproptosis can regulate glutathione-induced ferroptosis by modulating the protein ferredoxin 1. There is partial crosstalk between disulfidptosis and ferroptosis; under glucose deprivation, upregulation of solute carrier family 7 member 11 consumes NADPH, leading to abnormal accumulation of disulfide compounds and promoting disulfidptosis in neurons. Mixed lineage kinase domain-like pseudokinase, a key participant in necroptosis, is also associated with activation of the pyroptosis-related protein NLRP3 inflammasome, further promoting neuronal pyroptosis during necroptosis in ischemic stroke. Neutrophil extracellular trap-related death in ischemic stroke is mainly caused by citrullination, stress-triggered neutrophil extracellular trap formation, and inflammatory responses mediated by release of various cytotoxic proteases. Other emerging subtypes such as immunogenic cell death cause neuronal damage in ischemic stroke through various specific mechanisms.
Acta Biochimica et Biophysica Sinica•2025•DOI: 10.3724/abbs.2025145
Angiopoietin-like 4 (ANGPTL4) is elevated in wound tissue and contributes to wound healing, but the mechanisms remain unclear. This study demonstrates that ANGPTL4 expression is significantly increased in epidermal stem cells (EpSCs) in the periwound epidermis during murine wound healing. Increased Angptl4 expression positively correlates with elevated levels of tumor growth factor-α, interleukin-1β, epidermal growth factor, nerve growth factor, fibroblast growth factor 7, and transforming growth factor-β1, each of which induces Angptl4 in EpSCs. RNA sequencing of EpSCs from wild-type and Angptl4 knockout (Angptl4–/–) mice reveals altered expression of cell cycle and proliferation genes, including decreased cyclin E2/A2/B1 and cyclin-dependent kinase 1 (Cdk1), increased Cdk inhibitor 2a (Cdkn2a) and Cdkn2b, and reduced prolactin (PRL) family members Prl2a1, Prl8a1, Prl8a9, and Prl8a6. Mechanistically, ANGPTL4 stimulates EpSC proliferation via PRL8a6-mediated upregulation of cyclins A2/E2/B1 and Cdk1, downregulation of Cdkn2a, and acceleration of G1 to S and G2 phase progression. In vivo, Prl8a6 mRNA is upregulated by ANGPTL4 in mouse periwound tissue during healing. Knockdown of Angptl4 or Prl8a6 impairs EpSC proliferation and delays re-epithelialization. These findings establish that after skin injury, proinflammatory cytokines and growth factors stimulate Angptl4 in EpSCs, and ANGPTL4 promotes EpSC proliferation by increasing Prl8a6, thereby accelerating wound re-epithelialization.